Every year, about 100 million adult Americans experience some form of pain, a condition that costs the nation between $560 billion and $635 billion annually in lost productivity and treatment. The recently released `National Pain Strategy' developed by the NINDS's IPRCC, recognizes acute and chronic pain as a serious and costly public health issue, and articulates that new treatment approaches need to be developed to reduce the burden of pain in the US. Opioid analgesics are the mainstay of pain treatment and often the only treatment option that provides significant relief. However, opioid analgesics (which are mainly mu opioid receptor (MOP) agonists) are controlled substances that have abuse potential and are riddled with other side effects such as constipation, nausea, and tolerance, which impede their long-term safety and effectiveness. There is clearly a need for new analgesics that provide opioid-like efficacies without the liabilities of opioid pain-killers. he nociceptin opioid receptor (NOP), the 4th member of the opioid receptor family, and its endogenous peptide ligand, nociceptin/orphanin FQ (N/OFQ) are emerging new targets for pain medications. The NOP receptor and N/OFQ are found throughout in pain-processing pathways in the brain and spinal cord, and modulate opioid function by blocking opioid reward and even tolerance. We and others have shown that the natural peptide N/OFQ and small-molecule NOP agonists and bifunctional' NOP agonists with mu opioid agonist activity show potent analgesic effects on acute and chronic pain, are non-rewarding and do not develop tolerance. These findings suggest that NOP receptor agonists may be an attractive approach to obtain potent analgesic efficacies without opioid-related liabilities. In our Phase I project, we investigated th analgesic potential of NOP agonists in a transgenic mouse model of `sickle cell disease'(SCD), which develops spontaneous hyperalgesia similar to the condition in sickle patients. SCD is associated with severe pain, which remains a major challenge to treat. Opioids are the current standard of care, but due to side effects and development of tolerance, remain a sub-optimal approach to treat SCD pain, particularly when needed on a continued basis. Development of effective analgesics devoid of opioid liabilities would have a significant impact on pain treatment in SCD. Our Phase I studies showed that the NOP agonist-mu low efficacy agonist AT-200 showed significant antinociceptive efficacy in sickle mice, more potent and longer-lasting than high-dose morphine. AT-200 also showed a sustained analgesic effect, without tolerance development. These promising data that NOP agonists and/or NOP-mu bifunctional agonists are promising analgesics for treating chronic pain such as sickle pain. In this Phase II project we propose to conduct lead optimization and medicinal chemistry to identify novel NOP-targeted `preclinical lead candidates', which are optimized for their drug-like suitability and novelty, hav in vivo efficacy in pain models in rodents and nonhuman primates, and preliminary evaluation of toxicity, that are ready to be advanced into IND-enabling studies for development as pain medications.